Sex, comorbidities, and mortality in tricuspid regurgitation: Reassessing risk beyond valve severity

Introduction Severe tricuspid regurgitation (TR) is strongly associated with increased mortality, supported by robust clinical data. However, sex-related differences in the natural history and prognosis of TR remain inadequately characterized. Purpose To evaluate sex-related differences in outcomes among patients with varying degrees of TR severity. Methods Consecutive echocardiographic studies performed at a tertiary medical center between 2007 and 2025 were linked to clinical data. Patients were categorized into three mutually exclusive TR severity groups: mild, up to moderate, and significant (>moderate) TR, and further stratified by sex. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for all-cause mortality. Patients who underwent tricuspid valve interventions were excluded. Mediation analysis was performed to identify comorbidities that may account for sex-related differences in TR-associated risk. Results The final study cohort included 122,501 patients with a median age of 66 (IQR 53–77) years, of whom 43%were women. There were 61,191 (49.9%), 56,095 (45.8%), and 5,215 (4.25%) patients in the mild, up to moderate, and significant TR groups, respectively. Over a median follow-up of 10.2 (IQR 5.9–12.8) years, 32,796 (26.8%) patients died, with mortality increasing progressively with higher TR severity (all p<0.001). In univariate analyses, significant sex-related differences in TR-associated mortality were observed, with men exhibiting a higher excess risk (HR 4.56 vs. 3.89 for significant vs. mild TR in men vs. women, p for interaction <0.001). In contrast, after multivariable adjustment, TR-associated risk was similar in men and women (HR 1.57 vs. 1.50 for significant vs. mild TR in men vs. women; p for interaction not significant). Mediation analysis identified several comorbidities contributing to these sex-related differences, with the most prominent indirect effects related to chronic kidney disease (CKD; indirect OR 1.54) and heart failure with reduced ejection fraction (HFrEF; indirect OR 1.417). Conclusions Sex-related differences in mortality among patients with TR appear to be largely explained by differences in comorbidity burden rather than sex per se. The excess risk in men is mainly mediated by CKD and HFrEF, while TR severity remains an independent predictor of mortality in both sexes. These findings support risk stratification and management strategies focused on TR grade and comorbidity profile, rather than sex alone, and highlight CKD and HFrEF as key therapeutic targets in significant TR.